1. Field of the Invention
The cephalosporins of the present invention possess the usual attributes of such compounds and are particularly useful in the treatment of bacterial infections by oral administration.
2. Description of the Prior Art
A. Cephalosporins in General
Cephalothin and cephaloridine are well-known antibacterial agents; see U.S. Pat. Nos. 3,218,318, 3,449,338 and 3,498,979. The literature also contains considerable data on the activity of cephaloglycin and cephalexin; see U.S. Pat. Nos. 3,303,193, 3,507,861 and 3,560,489 and Great Britain Pat. Nos. 985,747 and 1,054,806. Newer cephalosporins include cefazolin and cephapirin; see U.S. Pat. No. 3,516,997 [and also Netherlands 68/05179 (Farmdoc 34,328) and South Africa 68/4513] and U.S. Pat. No. 3,422,100.
The literature on cephalosporins has been reviewed by E. P. Abraham, Quart, Rev. (London) 21, 231 (1967) by E. Van Heyningen, Advan. Drug Res., 4, 1-70 (1967) and briefly in Annual Reports in Medicinal Chemistry, Academic Press, Inc., 111 Fifth Avenue, New York, N.Y. 10003, by L. C. Cheney on pages 96 and 97 (1967) and by K. Gerzon and R. B. Morin on pages 90-93 (1968) and by Gerzon on pages 79-80 (1969) and by L. H. Conover on pages 101-102 (1970). New cephalosporins are frequently reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy as illustrated by Sassiver et al., Antimicrobial Agents and Chemotherapy --1968, American Society for Microbiology, Bethesda, Md., pages 101-114 (1969) and by Nishida et al., ibid, 236-242 (1970). Two excellent reviews are The Cephalosporins; Microbiological, Chemical and Pharmacological Properties and Use in Chemotherapy of Infection, L. Weinstein and K. Kaplan, Annals of Internal Medicine, 72, 729-739 (1970) and Structure Activity Relationships Among Semisynthetic Cephalosporins, M. L. Sassiver and A. Lewis, Advances in Applied Microbiology, edited by D. Perlman, 13, 163-236 (1970), Academic Press, N.Y. Two more recent reviews are .beta.-Lactam Antibiotics: Their Physicochemical Properties and Biological Activities in Relation to Structure, J. P. Hou and J. W. Poole, J. Pharmaceutical Sciences, 60(4), 503-532 (April, 1971) and Chemistry of Cephalosporin Antibiotics, R. B. Morin and B. G. Jackson, Fortschr. Chem. Org. Naturst, 28, 343-403 (1970) which includes a section on nucleophilic displacement of the acetate group at pages 370-373.
The preparation of various 7-[.alpha.-amino-arylacetamido]- cephalosporanic acids and the corresponding desacetoxy compounds in which aryl represents unsubstituted or substituted phenyl or 2- or 3-thienyl is described, for example, in British Specification Nos. 985,747, 1,017,624, 1,054,806 and 1,123,333, in Belgium Pat. No. 696,026 (Farmdoc No. 29,494), in U.S. Pat. Nos. 3,311,621, 3,352,858, 3,489,750, 3,489,751, 3,489,752, 3,518,260 and 3,575,969, in Japanese Pat. No. 16871/66 (Farmdoc 23,231), by Spencer et al., J. Med. Chem., 9(5), 746-750 (1966), by Ryan et al., J. Med Chem., 12, 310-313 (1969) and by Kurita et al., J. Antibiotics (Tokyo) (A) 19, 243-249 (1966) and see also U.S. Pat. No. 3,485,819. British Specification No. 1,073,530 includes a disclosure of the preparation of such compounds by acylation of silylated 7-ACA.
Netherlands Pat. Nos. 68/11676 (Farmdoc 36,349) and 68/12382 (Farmdoc 36,496) and U. S. Pat. Nos. 3,489,750 and 3,489,751 disclose ring-substituted cephaloglycins.
B. 3-Thiomethylcephalosporins
Various cephalosporins, including cephalosporin C on occasion but not cephaloglycin, have been reacted with nucleophilic, aromatic mercaptans to produce compounds having the structure ##STR1## In U.S. Pat. No. 3,278,531 Ar is phenyl or certain substituted phenyls or certain aromatic heterocyclic rings named, for example, in column 5. Similar nucleophiles, e.g. 2-mercaptopyrimidines, are disclosed in U.S. Pat. No. 3,261,832 and Great Britain No. 1,101,422 and U.S. Pat. Nos. 3,479,350 and 3,502,665, all issued to Glaxo. A parallel disclosure is found in Great Britain No. 1,109,525 to Ciba, e.g. in definition "h" for R.sub.3. Additional nucleophiles of this type were disclosed by Fujisawa In Belgium Pat. No. 714,518 (Farmdoc 35,307; Netherlands Pat. No. 68/06129 and South Africa Pat. No. 2695/68), in Canada Pat. No. 818,501 (Farmdoc 38,845), in Great Britain Pat. No. 1,187,323 (Farmdoc 31,936; Netherlands Pat. No. 67,14888), in U.S. Pat. No. 3,530,123 and in U.S. Pat. No. 3,516,997 (Farmdoc 34,328; Netherlands Pat. No. 68/05179) which includes the compound named cefazolin, which has a tetrazolylacetyl sidechain on the 7-amino group and a 5-methyl-thiadiazolylthiomethyl group at the 3-position and is described at some length in the scientific literature, e.g. in Antimicrobial Agents and Chemotherapy -- 1969, American Society for Microbiology, Bethesda, Md. at pages 236-243 and in J. Antibiotics (Japan) 23(3), 131-148 (1970).
Replacement of the 3-acetoxy group of a cephalosporin by various heterocyclic thiols has been disclosed in U.S. Pat. No. 3,563,983 and in Netherlands Pat. No. 70/05519 (Farmdoc 80,188R) where the sidechains were, for example, 7-.alpha.-aminophenylacetamido and typical heterocyclic thiols were 2-methyl-1,3,4-thiadiazole-5-thiol and 1-methyl-1,2,3,4-tetrazole-5-thiol.
Various cephalosporins having the structure ##STR2## in which acyl represents various sidechains including .alpha.-aminophenylacetyl have been described in some of the above and by Glaxo in Belgium Pat. No. 734,532 (Farmdoc 41,619) and in Belgium Pat. No. 734,533 (Farmdoc 41,620) and by Lilly in Belgium Pat. No. 743,754 (Farmdoc 41,150R).
Cephalosporins having the structure ##STR3## where X includes ##STR4## are disclosed in many patents including some of the above and in U.S. Pat. Nos. 3,239,516, 3,239,515, 3,243,435, 3,258,461, 3,431,259, 3,446,803, 3,278,531, 3,261,832 and 3,573,298.
Related publications in the scientific literature include J. Med. Chem. 8, 174-181 (1965) and J. Chem. Soc. (London) 1595-1605 (1965), 5015-5031 (1965) and 1959-1963 (1967).
C. 3-Acylthiomethylcephalosporins
The following publications and patents disclose certain additional 7-ACA derivatives containing a 3-acylthiomethyl moiety (in which phenyl is abbreviated as Ph):
1. G. F. H. Green, J. E. Page, and S. E. Staniforth, J. Chem. Soc., 1595-605 (1965). This reference gives the proton magnetic resonance spectra of the 3-benzoylthiomethyl derivative of cephalothin.
Cocker et al., J. Chem. Soc., 1142-1151 (1966) adds thiopicolinyl and references Belgium Pat. No. 650,444.
2. J. D. Cocker, et al., J. Chem. Soc., 5015-31 (1965) discloses compounds having the structure ##SPC1##
wherein R has the following meanings: PhCH.sub.2 --, ##STR5##
3. Glaxo's U.S. Pat. No. 3,261,832 discloses compounds having the structure ##SPC2##
wherein Y has, for example, the following meanings: ##SPC3##
R is CH.sub.3 O--, --NO.sub.2, --CN, CH.sub.3 S--, ##SPC4##
Equivalents are Netherlands Pat. No. 64/08066 (Farmdoc 15534) and Great Britain Pat. No. 1,101,424.
4. Glaxo's Netherlands Pat. No. 65/06818 (Farmdoc 19,306) discloses the reaction ##SPC5##
An equivalent is U.S. Pat. No. 3,502,665.
3. Glaxo's Netherlands Pat. No. 64/11521 [Chem. Abstr., 63: 13,281d (1965)] discloses the reaction ##STR6## wherein Y = --S--CO--Ph or ##SPC6##
Equivalents are Great Britain Pat. No. 1,101,422 and Canada Pat. No. 796,747 (Farmdoc 17362).
6. Ciba's U.S. Pat. No. 3,555,017 discloses compounds having the structure ##STR7## R.sub.1 and R.sub.2 = halogen.
As usual in Ciba's patents directed primarily to novel sidechains at the 3-position, the R group above is defined broadly as the residue of a carboxylic acid and may be illustrated by phenyl, as the residue of thiobenzoic acid. Equivalents are Belgium Pat. No. 708,241 (Farmdoc 33,276), Great Britain Pat. No. 1,211,747 and French Pat. No. 1,575,554.
7. Ciba's British Pat. No. 1,211,718 discloses compounds having the structure ##STR8## R as in 6 above.
Equivalents are Belgium Pat. No. 708,311 (Farmdoc 33,277) and U.S. Pat. No. 3,557,104.
8. Ciba's Belgium Pat. No. 751,526 (Farmdoc 90,178R) discloses compounds having the structure ##STR9## R as in 6 above.
An equivalent is Netherlands Pat. No. 70/08237.
9. Ciba's South Africa Pat. No. 69/8436 discloses compounds having the structure ##STR10## R as in 6 above.
Equivalents are Belgium Pat. No. 743,014 (Farmdoc 43,126R) and Netherlands Pat. No. 69/18611.
10. Ciba's South Africa Pat. No. 69/8399 discloses compounds having the structure ##STR11## R as in 6 above.
Equivalents are Belgium Pat. No. 742,933 (Farmdoc 41,568 R) and Netherlands Pat. No. 69/18531.
11. Ciba's South Africa Pat. No. 68/8185 discloses compounds having the structure ##STR12## R as in 6 above.
An equivalent is Netherlands Pat. No. 68/18868.
12. Ciba's Netherlands Pat. No. 68/18868 discloses compounds having the structure ##STR13## R as in 6 above.
Equivalents are South Africa Pat. No. 8120/68, German Pat. No. 1,817,121 and Belgium Pat. No. 726,316. 13. Fujisawa's Great Britain Pat. No. 1,187,323, for example, at page 5, lines 67-71 discloses compounds having the structure ##STR14## in which R represents methyl, thienyl, pyridyl, etc. and wherein general disclosure is made of other heterocyclic groups as at pages 1 and 2.
Equivalents are Netherlands Pat. No. 67/14888 (Farmdoc 13,936) and U.S. Pat. No. 3,530,123.
14. Fujisawa's Belgium Pat. No. 714,518 (Farmdoc 35,307) discloses (among many others) compounds having the structure ##STR15## wherein R is as 13 above.
Equivalents are Netherlands Pat. No. 68/06129 and South African Pat. No. 2695/68.
15. Glaxo's U.S. Pat. No. 3,243,435 and Belgium Pat. No. 650,444 (Farmdoc 15,535) disclose generally a vast variety of compounds having the structure ##STR16## wherein R.sup.2, is defined, e.g. in columns 1 and 4, to include various heterocyclic groups.
16. Ciba's South Africa Pat. No. 65/6950 (Farmdoc 22,192) discloses compounds having the structure ##STR17## in which R in Example 20 is phenyl.
Equivalents are Great Britain Pat. No. 1,109,525 and Canada Pat. No. 807,651.
17. Glaxo's U.S. Pat No. 3,479,350 discloses a process for producing 3-pyridiniummethyl cephalosporins which utilizes as an intermediate compounds of the type described in references 2 and 3 above.
18. Ciba's U.S. Pat. No. 3,757,013 discloses compounds of the formula ##SPC7##
wherein R.sup.3 is (lower) alkyl and R is as in 6 above.
19. Bristol's Belgian Pat. No. 795,811 (U.S. Pat. No. 3,743,644) discloses compounds of the general formula ##STR18## wherein Ar is phenyl, 2-thienyl or 3-thienyl; R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl or phenacyl; and Z is ##SPC8##
3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl.